Studies are proposed to use gene-targeted "knockout" mice to analyze the roles of different dopaminergic systems in the reinforcing effects of cocaine. Compelling pharmacological and neurobiologic evidence suggests that the abuse-related effects of cocaine are mediated by dopaminergic systems, and dopamine-based strategies provide promising avenues for development of new medications to treat cocaine abuse and dependence. The more specific identification of molecular targets for design and synthesis of dopamine-related medications may be greatly assisted by systematic analyses of mechanisms mediating cocaine's reinforcing effects in knockout mice. Although drugs acting at the dopamine transporter or at D1-like or D2- like receptors can modify some abuse-related effects of cocaine, the roles of these proteins in cocaine's effects are not fully understood. Genetic technology in mice that permits the deletion of a single protein by "knockout" of its functional gene provides a highly specific tool that may help to elucidate the roles pharmacologically. For example, the modification of cocaine self-administration by mixed D2/D3 compounds may be due to D2 or D3 actions alone or in combination. Studies in mice that lack the D2 receptor will permit a clearer analysis of the role of the D3 receptor in such effects. The proposed self-administration will: (1) examine the reinforcing effects of cocaine in mice lacking the dopamine transporter or to the D1 or D2 receptor, and (2) use these mice to specify more precisely the receptor mechanisms involved in the modification of cocaine self-administration by non-selective dopaminergic compounds. An important feature of this proposal is that self-administration studies in parental inbred strains and studies of responding maintained by a non-drug reinforcer will be conducted to provide a comprehensive basis for interpreting results of self-administration studies in knockout mice. In addition, studies in male and female mice will allow assessment of gender differences in genetic and pharmacological influences on cocaine self-administration. Overall, this research will increase our understanding of the roles of specific dopaminergic proteins in cocaine's abuse-related effects and help to identify the most appropriate targets for medications development. Moreover, integrating gene-targeting strategies with pharmacological and drug self-administration techniques will provide a framework for future studies using yet more advanced genetic technology to identify molecular mechanisms of cocaine's abuse-related effects.